Projects / Programmes
Molecular mechanisms of regulation of cellular processes related to some human diseases
January 1, 2018
- December 31, 2027
| Code |
Science |
Field |
Subfield |
| 1.05.00 |
Natural sciences and mathematics |
Biochemistry and molecular biology |
|
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 1.06 |
Natural Sciences |
Biological sciences |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
molecular mechanisms, regulation of cellular proceses, stress response, exosomes, model organisms, translational reseach, pharmacogenetics, personalized medicine
Data for the last 5 years (citations for the last 10 years) on
September 11, 2024;
A3 for period
2018-2022
| Database |
Linked records |
Citations |
Pure citations |
Average pure citations |
| WoS |
1,134 |
36,588 |
32,757 |
28.89 |
| Scopus |
1,108 |
41,576 |
37,410 |
33.76 |
Researchers (62)
Organisations (2)
Abstract
Mechanisms leading to activation of stress related pathways may be common to stress or age related diseases. With the aim to better understand the molecular mechanisms that regulate cellular processes in health and disease, our research programme combines basic and translational research, focusing on neurodegenerative diseases, hormone dependent diseases and cancer.
Basic research will focus on isolated enzymes, model organisms, cell lines and human tissues to improve the understanding of disease pathogenesis and support identification of new biomarkers or treatment targets. Novel methods will be developed for measuring BChE, PON1 and MPO enzyme activities and the association between their respective phenotypes and genotypes with clinical data will be determined in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) or Parkinson’s disease (PD).
The second part will focus on extracellular vesicles as endogenous delivery systems and potential biomarkers in human diseases. Fungi will be used as model system to study stress response pathways and cellular communication via extracellular vesicles as potential modulators of pathogenicity and as potential contributor to development of AD. The pathophysiological processes in neurodegenerative diseases may also be reflected in the concentration and molecular composition of extracellular vesicles in CSF or plasma. We will use novel approaches to screen the vesicles isolated from patients with MCI or AD for cargo molecules as potential early biomarkers.
In the translational part we will investigate novel targets and biomarkers of treatment response that will support earlier diagnosis, more effective treatment and personalized medicine. In neurodegenerative diseases, our aim is to identify genetic or other biomarkers of MCI to AD transition and develop predictive models that will enable early detection of patients with high risk to develop AD. We also aim to identify biomarkers of adverse events of dopaminergic treatment in PD and to develop models and actionable algorithms for patient stratification. In hormone dependent diseases we will investigate the formation of active estrogens from steroid precursors and progesterone metabolites f in model cell lines, tissue samples and blood samples of endometrial cancer and endometriosis patients to identify potential novel treatment targets and biomarkers for early diagnosis. In non-hormone -dependent cancers, we will focus on malignant mesothelioma (MM) and lung cancer. Our aim is to develop comprehensive clinical-pharmacogenetic models predicting treatment response in MM that would include genetic and serum biomarkers along with clinical data. With improved treatment selection algorithms more patients could be stratified into most effective treatment regimens. We will also investigate genetic and serum biomarkers to identify potential predictors for personalized treatment with immunotherapy, a novel treatment option in lung cancer.
Significance for science
There is increasing level of evidence, that in several human diseases, including the age- related disabilities and diseases, accumulation of molecular damage signals is linked to activation of stress response pathways and chronic inflammation, ultimatelly leading to activation of disease specific pathways and clinical manifestation of disease. Our research in this field is of great scientific importance, as recent reports indicate some shared common risk factors, molecular mechanisms and signalling pathways implicated in the development and the course of neurodegenerative diseases, type 2diabetes and its complications and certain cancers.
With the aim to better understand the molecular mechanisms that regulate cellular processes in health and disease, our research programme combines basic research on isolated enzymes, model organisms, cell lines and human tissues with translational research and clinical studies, with a particular focus on neurodegenerative diseases, hormone dependent diseases, and cancer.
Thus this programme continues the research on some core research topics, where our findings already made a major scentific impact and upgrades it with up to date methods and approaches for solving new research topics of high scientific relevance. Genomic, transcriptomic, proteomic, metabolomic and pharmacogenomic approaches will continue to contribute to better understanding of basic mechanisms implicated in molecular and cellular processes on several levels.
The basic research will contribute to the development of novel research methodologies and approaches that will enable novel scientific insights into mechanisms of enzyme reactions, signaling pathways and molecular mechanisms of stress response and disease pathogenesis. So far, we have been very sucessful in development of new solutions for the analysis of complex kinetic data for enzymatic reactions, that supported identification of novel potent inhibitors of human butyrilcholinesterases as potential drugs for Alzheimer's disease. Our approaches and methodologies are very interesting for other research groups as reflected in many excellent scientific collaborations and joint research papers. The studies of PON1 are also highly relevant, due to its potential role as a biomarker in inflammation, cardiovascular and neurodegenerative diseases.
The basic research constitutes the cornerstone for translational studies, designed to find new potential diagnostic and prognostic biomarkers. Exosomes, a form of extracellular membrane vesicles, have recently attracted a lot of interest in the field of biomarker research, as they represent an important means of communication between the cells in different organisms. In fungi, extracellular vesicles have been recently recognised as virulence factors in fungal infectivity and pathogenicity and linked to development of neurodegenerative diseases. In humans, they represent potential non-invasive biomarker in several diseases. We have already developed methods for isolation and characterisation of extracellular vesicles, so we will be able to use these approaches to contribute to the frontiers of research on the role of extracellular vesicles as endogenous delivery systems and biomarkers.
Also the research of hormone dependent disesase and cancer will expand the knowledge in the field of molecular endocrinology, especially with regards to novel mechanisms of steroid hormones action and contribute to identification of novel drug targets and development of noninvasive assays for early diagnosis. This research will be performed in collaboration with some of the leading groups in the field of molecular endocrinology of hormonedependent diseases.
In the field of pharmacogenetics, we have already made great scientific contribution in the research of genetic factors that lead to interindividul variability in drug metabolism, transport and targets as well as DNA repair mechanisms. We are the leading Slovenian research group in the field of pha
Significance for the country
The research program will have great impact on the development of undergraduate and graduate education. Most of the researchers in the programme group have a full teaching load as lecturers or teaching assistants, with only an additional 20% of employment for research. Among them
The fact that seven among them are full professors, indicates their outstanding achievements in the field of science, teaching and professional work. They are leading experts in their fields and by incorporating new scientific insights gained from their own research and from keeping up-to-date with the latest scientific literature, they contribute to the quality of education at the undergraduate and postgraduate level. The great potential of program group for the transfer of knowledge to doctoral students is reflected also in their great involvement in doctoral programmes of Biomedicine and Life Sciences, where they coordinate or participate in several core and elective subjects. They are also highly successful as mentors of doctoral theses; in the last 5 years they mentored and co-mentored 26 doctoral theses, which demonstrat the originality and novelty of our research.
Our programme will also have a big impact on health care. Translation of basic research to clinical applications constituts an important part of our programme. In the course of our clinical studies in the field of hormone related disorders, psychiatry, nevrology, inflamamtion and cancer, we have identified potential new diagnostic and prognostic markers, new targets for treatment as well as pharmacogenetic markers of response to treatment. When supported by replication and multicenter studies, our research will support the transition from the current treatments, based on the characteristics of the total patient population, to the predictive, preventive and personalized medicine.
The aim of pharmacogenetics in medicine is to improve the diagnosis, prognosis and treatment efficacy in individual patients taking into account his/hers genetic characteristics. Better understanding of genetic risk factors for diseases enables earlier identification of people at increased risk and faster diagnosis that allows earlier and more effective treatment. Pharmacogenetic testing can help to identify patients in which drug metabolism, transport and action are changed due to genetic variability in these pathways. Adjustment of the choice and dosage of medication and/or monitoring according to the patients demographic, clinical and genetic characteristics can improve the efficacy of treatment and reduce adverse events.
International Consortium for Clinical Implementation of Pharmacogenetics (CPIC), prof. Dolžan is a member of CPIC, has already prepared guidelines for adjusting the treatment with several drugs according to the patient's genotype. Applicability and economic viability of preemptive pharmacogenetic testing will be studied in the course of the H2020 U-PGX project. By participating in the U-PGX project we will acquire the knowledge, infrastructure and diagnostic kits needed to support faster implementation in clinical practice. Translation of our research into clinical practice is therefore also a major socio-economic impact. In addition to more effective treatment, which means big savings for health care system, also patients' quality of life of will significantly improve. It is however necessary, to agree on who will be the payer of such services for clinical practice.
Some of our research topic are also of great interest for industry. By solving the genomes of many extremophilic organisms, we can improve the biotechnological use of these microorganisms. Polyextremophilic yeast A. pullulans are involved in the biodegradation of plant material, plastics and aromatic compounds and has great potential for use in bioremediation, biotechnology and agronomy. In the genomes of halophilic fungi we also identified genes for rhodopsin the, which are extremely interesting for application in opt
Most important scientific results
Interim report
Most important socioeconomically and culturally relevant results
Interim report
